The BRCA2 c.7759C>T (p.Leu2587Phe; p.L2587F) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel classifies it as benign.1 This variant is present in gnomAD v2.1 and v4.1, with grpmax filter allele frequencies of 4.115e-05 and 4.535e-05, respectively; these values are above the ENIGMA BRCA2 BS1 Supporting threshold of 2.0e-05 and below the BS1 Strong threshold of 1.0e-04.2 In calibrated functional studies curated by the ENIGMA BRCA2 specification, this variant showed protein function similar to benign control variants, supporting BS3 at Strong strength.3 Computational evidence does not support a damaging effect under the ENIGMA BRCA2 rule because the BayesDel no-AF score is 0.147986 and the SpliceAI maximum delta score is 0.04, meeting BP4 thresholds for no predicted impact; REVEL is 0.73 but is not the operative ENIGMA BRCA2 threshold for this rule.4
Final classification
Likely Benign
BS1BS3BP4BP6
BRCA2
c.7759C>T
p.Leu2587Phe
This variant
The BRCA2 c.7759C>T (p.Leu2587Phe; p.L2587F) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel classifies it as benign.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework
Classification rationale
BS1BS3BP4BP6
Likely Benign
BRCA2 c.7759C>T
BS1 + BS3 + BP4 + BP6
→
Likely Benign
2
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
3
vcep_specifications_table9_v1_2_2024_11_18
4
bayesdelspliceai ↗revelvcep_specifications_v1_2_2024_11_18
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
BS1
supporting
review
Benign
This variant meets BS1 at Supporting strength because its filter allele frequency exceeds the ENIGMA BRCA2 BS1 Supporting threshold of 0.00002 but does not exceed the Strong threshold of 0.0001. In gnomAD v2.1, grpmax FAF is 4.115e-05, and in gnomAD v4.1, grpmax FAF is 4.535e-05.
gnomAD v2.1 grpmax FAF 4.115e-05gnomAD v4.1 grpmax FAF 4.535e-05BS1 Supporting threshold >0.00002 and ≤0.0001
BS3
strong
review
Benign
This variant meets BS3 at Strong strength. In the ENIGMA BRCA2 curated functional assay table, two calibrated studies reported protein function similar to benign control variants, supporting a benign functional interpretation.
Table 9 row for c.7759C>T / p.(Leu2587Phe) assigns BS3 StrongTwo calibrated studies cited by the VCEP table
BP4
supporting
review
Benign
This variant meets BP4 at Supporting strength under the ENIGMA BRCA2 computational rule. Codon 2587 is within the BRCA2 DNA-binding domain, BayesDel no-AF is 0.147986, which is at or below the BP4 threshold of 0.18, and SpliceAI shows a maximum delta score of 0.04, which is at or below the BP4 threshold of 0.1. REVEL is 0.73, but the official ENIGMA BRCA2 rule for this criterion uses BayesDel and SpliceAI.
Protein position 2587 is within the BRCA2 DNA-binding domainBayesDel no-AF score 0.147986SpliceAI max delta score 0.04
BP6
supporting
review
Benign
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
CSPEC/VCEP marked BP6 not applicableClinVar expert panel classification
Assessed · not applied
· 7 not met · 6 not assessed
Pathogenic
PS1
No qualifying evidence was identified showing that this variant has the same protein or splice consequence as a previously classified pathogenic or likely pathogenic BRCA2 variant under the ENIGMA BRCA2 rule.
PS3
Available calibrated functional evidence does not support a damaging effect.
PS4
No case-control study was identified showing a statistically significant enrichment of this variant in affected individuals compared with controls.
PM2
This variant is not absent from population controls.
PM3
No evidence was identified that this variant was observed with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 could not be evaluated.
PP1
No quantitative segregation data were identified showing that this variant co-segregates with disease in affected family members, so PP1 could not be applied.
PP3
Computational evidence does not meet the ENIGMA BRCA2 PP3 rule.
PP4
The BRCA2 clinical-history likelihood ratio for this variant is 0.5820637473 from 6 probands, which is below the ENIGMA BRCA2 PP4 Supporting threshold of 2.08.
Benign
BA1
Population frequency does not reach the ENIGMA BRCA2 BA1 threshold.
BS2
No qualifying data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would meet the ENIGMA BRCA2 BS2 point-based framework.
BS4
No quantitative lack-of-segregation data were identified showing that this variant fails to track with disease in affected relatives, so BS4 could not be applied.
BP1
This missense variant does not meet BP1 because codon 2587 is within the BRCA2 DNA-binding domain at amino acids 2481-3186, whereas the ENIGMA BRCA2 BP1 rule is for missense or silent variants outside a clinically important functional domain with no predicted splice effect.
BP5
The BRCA2 clinical-history likelihood ratio for this variant is 0.5820637473 from 6 probands, which is above the ENIGMA BRCA2 BP5 Supporting threshold of 0.48.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.64705e-05; MAF= 0.00465%, 75/1613928 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00282e-05; MAF= 0.00800%, 5/62478 alleles, homozygotes = 0); grpmax FAF= 4.535e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.37487e-05; MAF= 0.00437%, 11/251436 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.91362e-05; MAF= 0.00791%, 9/113728 alleles, homozygotes = 0); grpmax FAF= 4.115e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0046%
· 75 / 1,613,928
0 hom · FAF 0.0045%
0 hom · FAF 0.0045%
Remaining individuals 5 / 62,478 |
0.008% |
European (non-Finnish) 67 / 1,180,010 |
0.0057% |
Admixed American 2 / 59,996 |
0.0033% |
European (Finnish) 1 / 64,016 |
0.0016% |
+ 6 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0044%
· 11 / 251,436
0 hom · FAF 0.0041%
0 hom · FAF 0.0041%
European (non-Finnish) 9 / 113,728 |
0.0079% |
Admixed American 2 / 34,590 |
0.0058% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (6 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.73. BayesDel score = 0.147986.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links